Advanced Drug Delivery Reviews 144 (2019) 35–56 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Integrating nanomedicine into clinical radiotherapy regimens Allison N. DuRoss a, Megan J. Neufeld a, Shushan Rana b, Charles R. Thomas Jr. b,ConroySuna,b,⁎ a Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR 97201, USA b Department of Radiation Medicine, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA article info abstract Article history: While the advancement of clinical radiotherapy was driven by technological innovations throughout the 20th Received 2 May 2019 century, continued improvement relies on rational combination therapies derived from biological insights. In Received in revised form 2 July 2019 this review, we highlight the importance of combination radiotherapy in the era of precision medicine. Specifi- Accepted 2 July 2019 cally, we survey and summarize the areas of research where improved understanding in cancer biology will pro- Available online 4 July 2019 pel the field of radiotherapy forward by allowing integration of novel nanotechnology-based treatments. Keywords: © 2019 Elsevier B.V. All rights reserved. Cancer Drug delivery Radiation therapy Chemoradiotherapy Multimodal therapy Nanoparticles Dosing Contents 1. Introduction............................................................... 36 2. Advent,growth,andlimitationsofradiotherapy............................................... 36 2.1. Historyandadaptationtooncology................................................. 36 2.2. Equipment,technology,andclinicaldosingregimens......................................... 37 2.3. Currentlimitationsofradiotherapyandopportunities......................................... 38 2.3.1. Limitations........................................................ 38 2.3.2. Opportunities....................................................... 38 3. Landscapeofmultimodalradiotherapy................................................... 38 3.1. Chemotherapy........................................................... 38 3.2. Targetedtherapy.......................................................... 38 3.3. Immunotherapy.......................................................... 39 3.4. Limitationsandopportunitiesinmultimodalradiotherapy....................................... 39 4. Advancingmultimodalradiotherapythroughnanotechnology......................................... 39 4.1. Rationale/benefitsofnanomedicine................................................. 39 4.2. Applicationsofnanotechnologyinradiotherapy............................................ 40 4.3. Clinicallyapprovednanomedicine.................................................. 40 4.4. Typesofnanocarriers........................................................ 41 4.4.1. Liposomes........................................................ 41 4.4.2. Polymericcarriers..................................................... 42 4.4.3. Dendrimers........................................................ 42 4.4.4. Biomacromoleculesandconjugates............................................. 43 4.5. Currentstrategiesandconsiderationsfornanoparticlemultimodalradiotherapy............................. 44 4.5.1. Nanoparticle accumulation and the influenceofionizingradiationonthetumormicroenvironment................44 4.5.2. Enhancedtargetingthroughradiotherapyinducedexpression................................. 46 4.5.3. Radiotherapyandtheimmunesystem:Applicationsofnanotechnologytoradioimmunology...................47 ⁎ Corresponding author at: Department of Pharmaceutical Sciences, Oregon State University, 2730 SW Moody Ave, Portland, OR 97201-5041, USA. E-mail address: [email protected] (C. Sun). https://doi.org/10.1016/j.addr.2019.07.002 0169-409X/© 2019 Elsevier B.V. All rights reserved. 36 A.N. DuRoss et al. / Advanced Drug Delivery Reviews 144 (2019) 35–56 4.5.4. Pharmacokinetics/release..................................................48 4.5.5. Therapeuticmechanismofaction..............................................49 4.5.6. Dose/fractionation/timing/sequence.............................................50 4.6. Criticalconsiderationsforpreclinicalstudies.............................................51 4.6.1. Limitations and progress for In Vitro studies..........................................51 4.6.2. In Vivo studydesign....................................................51 4.6.3. Pre-clinicalradiotherapyphysicsparameters.........................................51 4.6.4. Translationofnanomedicines................................................52 4.6.5. Collaboration.......................................................52 5. Considerationsandconclusions.......................................................53 Acknowledgements..............................................................53 References...................................................................53 1. Introduction Looking to the future of oncology, the most promising advances in sur- vival and quality of life outcomes will likely emerge from further bio- Despite significant progress in the diagnosis and treatment of cancer, logic insight and subsequent engineering resulting in rational this collection of malignances remains one of the leading causes of combinations of radiation with other therapeutic strategies. death worldwide. Epidemiologic predictions by Siegel et al. estimated The continued advancement of nanotechnology in MMRT will de- that in 2019 there would be approximately 1.8 million new cancer diag- pend on both fundamental and translational research. However, the lat- noses and over 600,000 cancer-related deaths in the US alone [1]. These ter may not be as widely understood in the academic research high rates of incidence and mortality highlight the need for continued community. As such, the purpose of this review is to provide a brief advances in novel and more effective treatments. overview of CRT with a strong focus on the current clinical practice Currently, radiotherapy (RT) is a mainstay of oncology, serving both and its corresponding influence on nanoparticle drug delivery. as a first line treatment and used in combination with surgery and che- motherapy in many forms of cancer [2,3]. Although it is highly effective, its use is often viewed as a double-edged sword which does not discrim- 2. Advent, growth, and limitations of radiotherapy inate between healthy and diseased tissue [4,5]. As such, one of the big- gest challenges associated with RT is determining the effective dose for Soon after discovery by Röntgen in 1895, X-rays were quickly killing malignant cells without incurring collateral damage to healthy adapted for use in oncology as its therapeutic efficacy became clear in tissues. As this technology driven discipline has evolved from archaic the first patients treated [8,9]. However, the early biomedical applica- lead shielding to multileaf collimators (MLCs) and artificial tions of IR frequently resulted in undesirable side-effects garnering a intelligence-guided treatment plans, engineering advancements have public fear of radiation [10]. Later scientific innovation including signif- vastly improved the safety, accuracy, and efficacy of RT. However, as icant advancements in radiation dose planning and instrumentation im- the great progress in medical physics and technology-based innovation proved overall delivery accuracy and presented control over various begins to plateau, new multidisciplinary areas must be explored to fur- aspects of IR. Currently, oncologic standard of care comprises three ther widen the therapeutic window of RT. Importantly, radiation oncol- main treatment options; surgical resection, RT, and systemic therapy, ogists are well-equipped to adopt innovative new technologies, such as utilized individually or in various combinations [2]. Overall, 50% of pa- nanomedicine, based on the ever-evolving space in which they practice. tients are estimated to receive RT at some point during their treatment While the success of RT can be attributed to the technological ad- [11]. Ultimately, while RT is an effective therapeutic strategy, it still has a vancements made over the past decades, recent successes lie with the narrow therapeutic index, is primarily limited to localized disease, and combination of chemotherapy, targeted therapy, and immunotherapy may induce secondary malignancies [6–8]. with radiation therapy (i.e., multimodal radiotherapy or MMRT) [6]. In its essence, MMRT capitalizes on the quick succession of decisive blows that add to the primary damage which left a target vulnerable. 2.1. History and adaptation to oncology Thus, the sequence and time in which systemic agents and ionizing ra- diation (IR) are administered during MMRT are as important in treat- After the initial observation that X-rays could effectively treat other- ment efficacy as the therapeutic doses. For example, concurrent wise inoperable malignancies, the field of radiation oncology grew rap- chemoradiotherapy (CRT) has proven superior to sequential treatment idly. Illustrated in Fig. 1, the 1900s saw continual technologic and demonstrated improved survival in many cancers. However, con- advancements related to treatment planning and control over dose de- comitant therapy oftentimes further increases the toxic burden on the livery resulting in an exquisite reduction in adverse side-effects from patient [6]. treatment. However, since its inception, determining the optimal